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Relationships Between Age And White Matter Integrity In Children With Phenylketonuria, Erika M. Wesonga

Arts & Sciences Electronic Theses and Dissertations

Objective: Phenylketonuria (PKU) is a hereditary metabolic disorder associated with cognitive compromise. Diffusion tensor imaging (DTI) has allowed detection of poorer microstructural white matter integrity in children with PKU, with decreased mean diffusivity (MD) in comparison with healthy children. However, very little research has been conducted to examine the trajectory of white matter development in this population. The present study investigated potential differences in the developmental trajectory of MD between children with early- and continuously-treated PKU and healthy children across a range of brain regions.

Methods: Children with PKU (n = 31, mean age = 12.2 years) were …

Spatial And Epigenetic Regulation Of T-Cell Receptor Beta Gene Assembly, Kinjal Majumder

Arts & Sciences Electronic Theses and Dissertations

The adaptive immune system endows mammals with a sophisticated mechanism to recognize foreign proteins via surface antigen receptors that are expressed on the surface of all lymphocytes. This defense network is generated by V(D)J recombination, a set of sequentially controlled DNA cleavage and repair events that assembles functional antigen receptor genes from distally located Variable (V), Diversity (D) and Joining (J) gene segments. However, the recombination process must be stringently regulated to prevent formation of chromosomal translocations, which can lead to tumors. The process of V(D)J recombination is controlled at the levels of tissue, stage and allele specificity by a …

Flap Endonuclease 1 Promotes Telomere Replication And Stability By Distinct Mechanisms On The Leading And Lagging Strands, Daniel Cole Teasley

Arts & Sciences Electronic Theses and Dissertations

High fidelity DNA replication is essential for genomic stability and cell survival; this fact is underscored by the redundancy present in DNA replication and repair pathways. The complexity of these pathways is most evident at challenging DNA templates, such as those with repetitive sequence and transcribed loci. Among these challenging templates are telomeres, which are terminal, highly repetitive sequences that maintain genomic stability by preventing aberrant end-to-end chromosome fusions. In the absence of accurate, complete telomere replication, genomic instability results, ultimately leading to cell death or transformation. Here, we describe two unique roles in telomere stability for the DNA replication …

Physical Activity And Maternal And Neonatal Outcomes In Obese Pregnant Women, Rachel Ann Tinius

Arts & Sciences Electronic Theses and Dissertations

Maternal obesity and physical inactivity during pregnancy are independently associated with unfavorable maternal and neonatal metabolic outcomes. Previous research in non-gravid adults suggests physical activity provides protection from many chronic diseases irrespective of body weight. The primary purposes of this dissertation were to determine the impact of obesity on maternal metabolic health (lipid metabolism, inflammation, insulin resistance) and neonatal metabolic health (adiposity, inflammation, insulin resistance), and to determine if adverse maternal and neonatal metabolic health is improved in obese pregnant women who are physically active during pregnancy compared to sedentary obese women. The secondary purpose of this dissertation was to …

The Role Of Tmem178 In Regulation Of Osteo-Immune Activation And Inflammatory Bone Loss, Corinne Elaine Decker

Arts & Sciences Electronic Theses and Dissertations

Pathological bone loss in human disease such as arthritis is largely due to excessive osteoclast recruitment as a consequence of localized inflammation. Innate immune cells, namely neutrophils and macrophages, infiltrate the joint space and release pro-inflammatory cytokines as well as proteases to drive local tissue damage and inflammation. Importantly, IL-1 and TNF-a in particular act on the synovial fibroblasts as well as directly on osteoclast precursors to potently augment osteoclast differentiation and thus bone resorption. Current therapeutics to treat pathological bone loss are widely unsuccessful at targeting both the resorptive and inflammatory components of disease. We have previously demonstrated that …

Escherichia Coli Iron Acquisition Paradigms And Host Responses In The Human Urinary Milieu, Robin Reid Shields-Cutler

Arts & Sciences Electronic Theses and Dissertations

Urinary tract infections (UTIs) are some of the most common bacterial infections worldwide and are increasingly complicated by high antibiotic resistance and recurrence rates. Explanations for the marked individual differences in UTI susceptibility remain incomplete. In this thesis we show that urinary colonization by uropathogenic E. coli (UPEC) is influenced by urine composition and the activity of an important innate immune protein, siderocalin (SCN; also called lipocalin 2 or neutrophil gelatinase-associated lipocalin/NGAL). During UTI, host factors limit the availability of iron, an essential nutrient for the invading pathogen. In response, UPEC modify the urinary environment with metal binding siderophores, some …

Peripheral And Central Mechanisms Of Temporal Pattern Recognition, Christa Ann Baker

Arts & Sciences Electronic Theses and Dissertations

Encoding information into the timing patterns of action potentials, or spikes, is a strategy used broadly in neural circuits. This type of coding scheme requires downstream neurons to be sensitive to the temporal patterns of presynaptic inputs. Indeed, neurons with temporal filtering properties have been found in a wide range of sensory pathways. However, how such response properties arise was previously not well understood. The goal of my dissertation research has been to elucidate how temporal filtering by single neurons contributes to the behavioral ability to recognize timing patterns in communication signals.

I have addressed this question using mormyrid weakly …

Characterizing And Modeling Antibiotic Resistance Dynamics In Diverse Microbial Communities, Molly Krisann Gibson

Arts & Sciences Electronic Theses and Dissertations

Complex microbial communities colonize every habitat investigated to date, including soil, animals, water, and humans, as well as the structures we live in. It has been hypothesized that there is network of exchange allowing both bacterial organisms and functions to seamlessly move between and within these environments. These microbial communities often serve essential and beneficial functions for the host organism or environment. This is particularly evident in the human gut, where microbial communities consistently provide a set of services to its human host, including protecting against enteric pathogens, liberating nutrients from food, and signaling immune system regulation. However, these communities …

Β-Lactamase Gene Exchange Within The Enterobacteriaceae, Mitchell William Pesesky

Arts & Sciences Electronic Theses and Dissertations

Antibiotic resistance represents a grave threat to modern medicine’s control over infectious disease. Pathogens of the Enterobacteriaceae have proven particularly problematic as they can cause a wide variety of infections, and they can be, in some cases, resistant to all antibiotics recommended for use against them. A major part of the threat posed by the Enterobacteriaceae is their ability to exchange resistance genes by horizontal gene transfer (HGT). HGT has allowed some Enterobacteriaceae to quickly accumulate resistance against diverse antibiotics, and then to spread their resistance gene collection to other pathogenic strains. I explore three aspects of how HGT has …

Functional Identification And Characterization Of Cis-Regulatory Elements, Christopher Michael Fiore

Arts & Sciences Electronic Theses and Dissertations

Transcription is regulated through interactions between regulatory proteins, such as transcription factors (TFs), and DNA sequence. It is known that TFs act combinatorially in some cases to regulate transcription, but in which situations and to what degree is unclear.

I first studied the contribution of TF binding sites to expression in mouse embryonic stem (ES) cells by using synthetic cis-regulatory elements (CREs). The synthetic CREs were comprised of combinations of binding sites for the pluripotency TFs Oct4, Sox2, Klf4, and Esrrb. A statistical thermodynamic model explained 72% of the variation in expression driven by these CREs. The high predictive power …

Programming The Myocardium: The Notch-Wnt Axis, Benjamin S. Gillers

Arts & Sciences Electronic Theses and Dissertations

Heart related deaths are the number one cause of death in the United States. While heart failure and other mechanical issues are common, arrhythmias account for the majority of these deaths. By understanding the genetic architecture that patterns the normal cardiac conduction system, we can further deepen our understanding of how arrhythmias arise and develop targeted therapies to treat this deadly class of disease. I have found that canonical Wnt signaling is necessary for development of the atrioventricular junction. Furthermore, absence of myocardial Wnt signaling leads to tricuspid atresia. Overexpression of Wnt signaling leads to development of ectopic atrioventricular junction …

Neural Basis Of Functional Connectivity Mri, Jingfeng Li

Arts & Sciences Electronic Theses and Dissertations

The brain is hierarchically organized across a range of scales. While studies based on electrophysiology and anatomy have been fruitful on the micron to millimeter scale, findings based on functional connectivity MRI (fcMRI) suggest that a higher level of brain organization has been largely overlooked. These findings show that the brain is organized into networks, and each network extends across multiple brain areas. This large-scale, across-area brain organization is functionally relevant and stable across subjects, primate species, and levels of consciousness.

This dissertation addresses the neural origin of MRI functional connectivity. fcMRI relies on temporal correlation in at-rest blood oxygen …

Host Immune Signals Regulate Blood-Brain Barrier Function During Central Nervous System Infection And Autoimmunity, Brian Daniels

Arts & Sciences Electronic Theses and Dissertations

A major hallmark of neuroinflammatory diseases is the breakdown of the blood-brain barrier (BBB). This barrier between the hematogenous circulation and the parenchyma of the central nervous system (CNS) is a multicellular interface made up of endothelial cells joined by tight and adherens junctions (TJs and AJs), along with pericytes and the endfeet projections of astroglia. Together, these cells tightly restrict the movement of solutes and cells from the circulation into the CNS in a manner crucial for proper CNS homeostasis. Regulation of BBB function occurs dynamically during neuroinflammatory diseases such as infection and CNS autoimmunity, resulting in both protective …

Evolutionary Developmental Leaf Morphology Of The Plant Family Araceae, Claudia Liliana Henriquez

Arts & Sciences Electronic Theses and Dissertations

Studying the evolutionary developmental morphology of leaves using next-generation phylogenetics, a candidate gene approach and comparative developmental studies in the plant family Araceae is the overarching theme of the dissertation.

The plant family Araceae is an ancient lineage from the Early Cretaceous and belongs to the monocotyledons. Members of Araceae display striking variation in leaf development; such variation contradicts traditional models of monocot leaf development. Additionally, dissected leaves, which are rare in monocots, seem to have evolved independently multiple times in Araceae by various developmental mechanisms.

Despite extensive efforts to elucidate the evolutionary history of Araceae, phylogenetic ambiguity in the …

A Novel Cholesterol-Independent Mode Of Binding Promotes Cytolysin-Mediated Translocation And Pore Formation By Streptolysin O, Cara Mozola Forsberg

Arts & Sciences Electronic Theses and Dissertations

Effector translocation is a common strategy used by bacteria to promote pathogenesis via disruption of the immune response, prevention of phagocytosis, or induction of toxicity in the infected cell. The Gram-positive bacterium Streptococcus pyogenes utilizes a unique effector translocation system termed cytolysin-mediated translocation (CMT) to introduce the NAD+ glycohydrolase SPN into host cells during infection, resulting in cytotoxicity. Host cell membrane recognition by the cholesterol-dependent cytolysin (CDC) Streptolysin O (SLO) is a requisite step in this process, but the canonical cholesterol-dependent pore-forming activity of SLO is unnecessary, indicating that SLO is a bifunctional toxin. SLO exhibits extensive homology to other …

A Gnotobiotic Mouse Model For Studying The Effect Of Human Gut Community Ecology On A Pathobiont, Bacteroides Fragilis, Vitas Wagner

Arts & Sciences Electronic Theses and Dissertations

ABSTRACT OF THE DISSERTATION

A Gnotobiotic Mouse Model for Studying the Effect of Human Gut Community Ecology on a Pathobiont, Bacteroides fragilis

by

Vitas Wagner

Doctor of Philosophy in Biology and Biomedical Sciences

Evolution, Ecology, and Population Biology

Washington University in St. Louis, 2015

Professor Jeffrey I. Gordon, Chair

Childhood undernutrition represents a pressing global health challenge. Epidemiologic studies have shown that undernutrition is not due to food insecurity alone, but rather represents a complex set of interactions between intra- and intergenerational factors. The gut microbiota has been implicated as one such factor. This thesis tested the hypothesis that enteropathogen …

Essential Roles Of Stat3 In Zebrafish Development, Yinzi Liu

Arts & Sciences Electronic Theses and Dissertations

Vertebrate gastrulation is a fundamental morphogenetic process during which germ layers are formed, patterned and shaped into a body plan with organ rudiments. Among the conserved gastrulation movements, convergence and extension (C&E) occur concurrently to narrow the germ layers mediolaterally and elongate them along the anteroposterior embryonic axis. C&E are largely driven by cell migration and cell intercalation, while cell proliferation has been considered dispensable and even incompatible with gastrulation movements and morphogenesis. Signal transducer and activator of transcription 3 (Stat3) has been implicated by antisense morpholino loss-of-function study in regulation of zebrafish C&E movements in part by promoting non …

Dissection Of Affective Catecholamine Circuits Using Traditional And Wireless Optogenetics, Jordan Gary Mccall

Arts & Sciences Electronic Theses and Dissertations

Parsing the complexity of the mammalian brain has challenged neuroscientists for thousands of years. In the early 21st century, advances in materials science and neuroscience have enabled unprecedented control of neural circuitry. In particular, cell-type selective manipulations, such as those with optogenetics and chemogenetics, routinely provide answers to previously intractable neurobiological questions in the intact, behaving animal.

In this two-part dissertation, I first introduce new minimally invasive, wireless technology to perturb neural activity in the ventral tegmental area dopaminergic system of freely moving animals. I report a series of novel devices for studying and perturbing intact neural systems through optogenetics, …

Neural Mechanisms Of Working Memory Cortical Networks, Charalampos Papadimitriou

Arts & Sciences Electronic Theses and Dissertations

This dissertation is aimed at understanding the cortical networks that maintain working memory information. By leveraging patterns of information degradation in spatial working memory encoding we reveal new neural mechanisms that support working memory function and challenge existing models of working memory circuits.

First we examine how interference from previous memoranda influences memory of a currently remembered location. We find that memory for a currently remembered location is biased toward the previously memorized location. This interference is graded, not all-or-none. Interference is strongest when the previous and current targets are close and activate overlapping populations of neurons. Contrary to the …

The C-Terminal Linker Of Ftsz Acts As An Intrinsically Disordered Peptide During Cell Division In Bacillus Subtilis, Steven Grigsby

Undergraduate Theses—Unrestricted

The bacterial tubulin homologue FtsZ polymerizes in vitro in a GTP-dependent manner to form long, single stranded filaments. In cells, these filaments assemble at the nascent division site, interacting laterally to form the contractile Z ring. The Z ring serves as a scaffold for the rest of the division machinery and constricts at the leading edge of the invaginating septum during cytokinesis. The FtsZ polypeptide consists of three primary domains: the N-terminal globular core consisting of 315 residues that contains the GTP binding site, a variable and flexible C-terminal linker (CTL) consisting of 50 residues, and a conserved region at …

Phylogenetically Novel Species Are More Successful Due To High Competitive Ability At Local And Regional Scales, Amy C. Patterson

Senior Honors Papers / Undergraduate Theses

While few introduced exotic species become invasive, this small number of species poses serious threats to biodiversity, ecosystem function, and recreation, leading ecologists to study why certain species become invasive and why certain communities are prone to invasions. Several leading hypotheses seek to explain invasiveness, including the Enemy Release Hypothesis, the trait superiority hypothesis, and the Biotic Resistance Hypothesis, but none are consistently supported in the literature. We suggest that the lack of uniting hypothesis is a result of the inability to put multiple proposed mechanisms in the same framework, and suggest for a uniting framework Darwin’s Naturalization Hypothesis along …

Investigating The Role Of Wolbachia Endosymbionts In The Expansion Of The F Element In Drosophila Ananassae, Elizabeth J. Chen

Undergraduate Theses—Unrestricted

At 4.2 Mb overall, the Drosophila melanogaster Muller F element (dot chromosome) is an unusual autosome; it is broadly heterochromatic, but the distal 1.3 Mb has a gene density and expression pattern similar to other autosomes. More intriguing is the large expansion of the D. ananassae F element (~20 Mb). Elucidating the factors that contribute to this expansion could improve our understanding of how heterochromatic domains are maintained and amplified.

Previous analyses show that the lateral gene transfer (LGT) of Wolbachia (the most widespread intracellular bacteria in the Rickettsiales order) into the D. ananassae genome is an important contributor to …

Pharmacology Of Organic Cation Transporters: Focus On Structure-Function Relationships In Oct3 (Slc22a3), Dan C. Li

Undergraduate Theses—Unrestricted

Organic Cation Transporters (OCTs) are polyspecific, facilitative transporters that play major roles in metabolite and drug clearance. OCTs are promising drug targets and elucidating their mechanisms of substrate recognition is crucial for rational drug design. OCT-mediated transport of polyvalent cations remains unexplored. OCT-expressing Xenopus laevis oocytes were used to assess transport of polyamines, ubiquitous polyvalent cations of broad physiological import, but for which transport mechanisms are unknown. Dose-response analysis of radiolabelled substrate uptake revealed that polyamines are relatively low affinity, but high turnover substrates for OCTs compared to model substrate methyl-4-phenylpyridinium (MPP⁺). Polyamine analogs of varying hydrophobic character …

Functional Consequences Of Cd4+ T Cell Receptor Ligation In The Immune Response To Listeria Monocytogenes, Stephen Phillip Persaud

Arts & Sciences Electronic Theses and Dissertations

Interactions between the ab T cell receptor (TCR) and peptide-bound MHC molecules (pMHC) are highly specific and sensitive despite low affinities. The basis of TCR ligand specificity and its functional manifestations during protective immune responses are incompletely understood. To study this, we have generated two TCR transgenic mice called LLO56 and LLO118, which bear CD4+ T cells that recognize the same dominant epitope from the virulence factor Listeriolysin O (LLO) of Listeria monocytogenes. These TCRs were cloned from Listeria-infected B6 mice, and thus represent two solutions to recognizing the same pathogen-derived pMHC. LLO118 T cells expanded better than LLO56 during …

Excessive Complement Activation Due To Genetic Haploinsufficiency Of Regulators In Multiple Human Diseases, Michael Triebwasser

Arts & Sciences Electronic Theses and Dissertations

The complement system is an ancient and powerful form of innate immunity. The alternative pathway (AP), a positive feedback loop, is at the core of the complement system. Activating components and regulators of the AP are genetically implicated in atypical hemolytic uremic syndrome (aHUS) and age-related macular degeneration (AMD). aHUS features kidney failure, and often affects young children, but may occur throughout life and can be precipitated by pregnancy. aHUS associated variants are extremely rare and are considered highly penetrant. At the opposite end of the spectrum, AMD affects the retina leading to loss of central vision with a late …

Viral And Innate Immune Factors Controlling Disease Susceptibility During Chikungunya Virus Infection, Anjali Rohatgi

Arts & Sciences Electronic Theses and Dissertations

Chikungunya virus (CHIKV) is a re-emerging pathogen that causes a high fever, painful arthritis and a macular rash. The current outbreak began in Kenya in 2004 and spread throughout the Indian Ocean area and Southeast Asia, infecting millions. During this outbreak, more severe disease manifestations, including lethality, were reported for the first time. To understand one possible reason for this change in severity, we explored the impact of genetic changes in the virus on disease pathogenesis. In addition, we dissected the role of type I interferon (IFN) subtypes in CHIKV infection. From these studies, we have gained important insight into …

The Intrinsic Apoptotic Cascade In Hematopoiesis And Susceptibility To Therapy-Related Leukemia, Elise Peterson Lu

Arts & Sciences Electronic Theses and Dissertations

Apoptosis and the DNA damage response have been implicated in hematopoietic development and differentiation, as well as in the pathogenesis of myelodysplastic syndrome (MS) and leukemia. However, the specific roles of direct mediators of apoptosis, such as caspases, in hematopoiesis and leukemogenesis have not been elucidated. In order to address this, we studied the effects of loss of Caspase-9, the initiator caspase of the intrinsic apoptotic cascade, and Apaf1, the key component of the apoptosome, on fetal and adult hematopoiesis. We first found that loss of these key regulators has significant effects on the hematopoietic stem and progenitor compartment, with …

The U1a/U2b"/Snf Family Of Rna Binding Proteins: Evolution Of Rna Binding Specificity And Contributions Of Heterotropic Linkage To Snrnp Protein Partitioning, Sandra Gisela Williams

Arts & Sciences Electronic Theses and Dissertations

The U1A/U2B"/SNF is a family of RNA binding proteins that is a highly conserved throughout eukaryotes. These proteins are found in the U1 and/or U2 splicing snRNPs (small nuclear ribonucleoprotein particles). In humans, U1A and U2B" specifically bind to the U1 and U2 snRNAs, respectively. The Drosophila genome codes for SNF, an essential protein that localizes to both the U1 and U2 snRNP. While a specific splicing functions for these proteins have not been determined, their conserved snRNP localization suggests an important splicing-related function.

The difference in protein number and partitioning between Drosophila and humans suggested that these proteins may …

Are There Multiple Kinds Of Episodic Memory? An Fmri Investigation Comparing Autobiographical And Recognition Memory Tasks, Hung-Yu Chen

Arts & Sciences Electronic Theses and Dissertations

What brain regions underlie retrieval from episodic memory? The bulk of research addressing this question has relied upon laboratory-based recognition memory. Another, less dominant tradition has employed autobiographical methods, whereby people recall events from their lifetime, often after being cued with words or pictures. Previous research comparing regions underlying successful memory retrieval between these two methodological approaches has shown mixed results. To examine the neural processes underlying recognition memory for materials encountered in the laboratory and autobiographical memory, we conducted a within-subject study using fMRI. We showed participants indoor and outdoor scenes under two types of instructions: In the lab-based …

Molecular Characterization Of A Novel, Highly Protective Combination Monoclonal Antibody Therapy Against Chikungunya Virus, Pankaj Pal

Arts & Sciences Electronic Theses and Dissertations

Chikungunya virus (CHIKV) is an Aedes mosquito-transmitted alphavirus that causes epidemics of a debilitating, often chronic polyarthritis in humans. Over five million people in Africa and Asia have been infected since 2005, and an outbreak occurred recently in Italy demonstrating the potential for a global epidemic. A strong antibody response is elicited during infection and the aim of this thesis was to develop a better understanding of how the humoral immune response can control CHIKV infection. We identified 230 new anti-CHIKV monoclonal antibodies (MAbs) and tested their ability to inhibit infection of strains representing all three CHIKV genotypes (East/Central/South African, …